AACR Round Up: Immunotherapy, Breast Cancer, and Beyond

By Neil Canavan

There’s no question that the landscape of the annual meeting of the American Association for Cancer Research (AACR) is evolving.

“I’ve witnessed a tremendous change in the content and tone of this meeting over the years,” said Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C. “It’s become far more translationally oriented… It’s a very exciting time.”

A principle source of that thrill is the juggernaut of innovations collectively known as cancer immunotherapy.

The present data originated from a phase I study initiated in 2008, where heavily pretreated metastatic melanoma patients received nivolumab every two weeks for up to two years. Initial results from this investigation were heralded as “unprecedented”.

Overall survival (OS) rates at 5 years were an astounding 34%. Prior to this, patients in this disease setting had a five year survival rate of roughly 16%. “Of note, there seems to be a plateauing (of survival curves) at a time period around 44 months,” said Hodi, implying that if treatment made it that far, hopes for an outright cure were not unreasonable.

There are even higher hopes for a greater improvement in survival outcomes when patients receive nivolumab as front-line treatment – a study that is currently underway. The reasoning is fairly straightforward: prior treatment negatively impacts the patient’s immune system, and nivolumab works best in tandem with an immune system that’s still intact.

Anti-PD-1 Inroads: Head and Neck Cancer, Merkel Cell

Nivolumab and pembrolizumab, both targeted to the PD-1 receptor, and both highly active in melanoma, lung, and kidney cancers, are now being tested in other tumor types.

In the phase III, CheckMate-141 study, reported by Maura Gillison, MD, PhD, Ohio State University Comprehensive Cancer Center, Columbus, OH, nivolumab demonstrated marked clinical activity in the Head and Neck Cancer disease setting where there is a profound unmet need.

“Head and neck cancer that progresses within 6 months of treatment with (standard of care) is a particularly devastating disease with an average survival of less than six months,” Gillison explained. “No anticancer agent has ever shown to improve survival for this patient population, and no new treatments have been approved for head and neck cancer for over a decade.”

In the CheckMate study patients with advanced head and neck cancer were randomized to nivolumab (n=240) or “physician's choice” (n=121). Physician’s choice represented standard of care (SOC) and could include treatment with docetaxel, methotrexate, or cetuximab. The primary endpoint for this investigation was OS.

As with the data on anti-PD-1 activity in melanoma, results from this study were equally impressive: After 12 months of follow-up, 36% of patients treated with nivolumab were alive as compared with 16.6% who received SOC. “This is something that has never been seen before in this patient population,” said Gillison. Median overall survival was 7.5 months for nivolumab vs. 5.1 months for SOC.

And the FDA has taken note. Less than 10 days after these results were reported, nivolumab was granted breakthrough designation for head and neck cancer.

In Merkel Cell Carcinoma (MCC), Paul Nghiem, MD, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA said, “There has not been a trial before that showed benefit in this cancer and there was actually a lot of doubt (in the field) that a trial could be carried out logistically.” In fact, given the annual rate of incidence MCC nationwide at 2000 cases, the disease nearly qualifies for orphan designation, and only recently was the main driver of the disease revealed.

In 2008 it was discovered that Merkel cell polyomavirus (MCPyV), a virus almost universally present on healthy skin, drives 80% of the cancer cases, which are typically diagnosed in patients over the age of 50. “It’s a fascinating story because this is a common virus in day care centers, on door knobs – we get exposed to it when we’re little kids and for some reason, five decades later, 1 in 3000 people will get Merkel cell carcinoma.”

There are currently no FDA approved therapies for MCC, with the current standard of care being a platinum agent plus etoposide. The historical response rate for this regimen is 55%, and is rarely durable, with 90% of patients progressing within 10 months.

In the present multicenter, single arm, open label, phase II investigation of unresectable or metastatic MCC, patients were treated with the anti-PD-1 drug, pembrolizumab (n=24).

Results of the study were highly encouraging, with an overall response rate of 56% observed, and two patients experienced a complete response. For the patients who tested positive for the MCPy virus, the response rate was even higher at 62%. Overall, these data translated to an impressive progression-free survival (PFS) of 9 months – with PFS often serving as a surrogate indication for eventual improvement in overall survival (OS) (Figure 1).

Of note, the expression of PD-L1 in a given MCC patient’s tumor – the ligand for the PD-1 receptor which is blocked by pembrolizumab – was not predictive of response, and therefore provides no guidance as to who would likely respond to this very expensive medication.

All the MAGE

Last but not least for IO, is a report on so-called adoptive cell therapy. The study highlighted here is an investigation of a novel construct identified as HLA-DPB1*401-restricted T-cell receptor targeting MAGE-A3.

“This is the first clinical trial testing an immunotherapy that uses gene-engineered CD4 T cells against metastatic cancer,” said Yong-Chen William Lu, a research fellow in the Surgery Branch at the NCI who works in the lab of Steve Rosenberg, a pioneering leader in the field of IO.

HLAs (human leukocyte antigens) are cell surface proteins that “display” antigenic proteins derived from the interior of the cell. This presentation is then interrogated by cells of the immune system that distinguish self (okay, password accepted, proceed on your way) from non-self (not okay, sign of infection – virus or bacteria, or dysfunction, like cancer – shoot on sight).

There are several HLA subtypes, with the HLA DPB1 *0401 subtype present in roughly 60% of Caucasians.

As for the MAGE detecting part of this genetic construct, MAGE-A3 is expressed on a variety of cancer cell types, and theoretically should not be present on healthy cells since MAGE-A3 is a member of the cancer/testis antigen family, proteins that are only expressed in germ line (embryonic), rather than somatic (adult tissue) cells.

The creation of the HLA therapeutic construct proceeds as follows: Healthy T cells are filtered out from the patient’s blood. The cells are genetically altered to express a T cell receptor that recognizes the HLA/MAGE complex present on tumor cells. The cells are then expanded ex-vivo to numbers ranging from millions to billions of cells which are then reintroduced into the patient.

The present investigation enrolled 14 metastatic cancer patients with a variant of tumor types. Results were modest in that there were only three partial responses observed, encouraging in that the currently red hot field of adoptive cell therapy is limited by a lack of efficacy in solid tumors. Therefore, these results have justified the planning of a phase II trial with this construct.

Progress for Breast Cancer, Targeted Therapies

Not to be drowned out by the din of IO presentations, were the impressive results from 2 studies in breast cancer: the MINDACT study, and I-SPY2.

Patients (n=6,693) were categorized as low or high risk for tumor occurrence according to the criteria of MammaPrint and Adjuvant! Online. Results showed that MammaPrint was able to identify patients who did not need adjuvant treatment 94.7% of the time.

“I’m assuming MammaPrint will become popular in the region of the world where it was developed (EU) and perhaps in other parts of the world,” said Martine Piccart, MD, PhD, head of the Medicine Department, Jules Bordet Institute, Brussels, Belgium. “But for the U.S. it’s a question mark because OncoType DX is really well established now.” (OncoType DX is another instrument to determine risk of breast cancer recurrence.)

I-SPY-2

While MammaPrint considers adjuvant treatment for breast cancer, the I-SPY-2 trial investigated the use of combination treatment with trastuzumab emtansine (T-DM1) and pertuzumab in the pre-surgery (neoadjuvant) setting.

“We know in the neoadjuvant setting that achieving a pathologic complete response (pCR) meaning, no tumor seen in the breast or the lymph nodes at the time of surgery, is an excellent surrogate for long-term survival outcomes,” said study presenter Angela DeMichele, MD, MSCE, professor of medicine and epidemiology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. “However, not every patient achieves a path-CR – the goal here is to find new therapies that will get you there.”

To that end, the I-SPY-2 trial randomized patients to neoadjuvant treatment arms of T-DM1/pertuzumab (n=52) vs. SOC of paclitaxel/trastuzumab (n=31). All patients additionally received doxorubicin and cytoxin and then proceeded to surgery.

Results showed that neoadjuvant treatment with of T-DM1/pertuzumab had a pCR in 52% of patients vs. 22% for SOC.

“This combination has a very different toxicity profile than the standard of care with Herceptin,” said DeMichele. “Neuropathy, hypertension, and alopecia were much less common, and I would argue that these are side effects that really matter to women, that really affect their day-to-day function.”

Given these results this novel combination was recommended to proceed to a phase III study.

Targeting Gene Fusions: Entrectinib

The small molecule drug, entrectinib, which targets genetically altered variants of the NTRK1/2/3, ROS1, and ALK proteins, has shown activity in several tumor types.

“Recurrent gene rearrangements are appealing targets for the small molecule world,” said the entrectinib study presenter, Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center, New York, NY. These rearrangements, often fusions of distinct sequences, result in constructs that spur the development of certain cancers.

In the present example, genes for a class of molecules called tyrosine kinases fuse with an upstream partner, “and what that does is provide dimerization domains that then result in ligand independent dimerization and activation of these downstream growth pathways,” explained Drilon. “It’s important to point out that these fusions are detectable in the clinic, and select fusions are clinically actionable. Response to targeted therapy can be very dramatic.”

Drilon tested entrectinib, in patients of several tumor types with the detected NTRK1/2/3, ROS1, or ALK gene alterations, in two separate phase I investigations (n=119).

Results from these early studies suggest that patients with NTRK1/3 alterations had an overall response rate (ORR) of 100% (n=3); ROS1 had an ORR of 86% (12/14), and for the patients with the ALK fusion an ORR of 57% was observed (4/7).

Importantly, the drug is known to have activity in the CNS, and those patients on study with CNS involvement had an ORR of 100% (3/3). This is of particular interest in non-small cell lung cancer cases with gene rearrangements where brain mets are commonly observed as the disease progresses.

Science!

Wrapping up this AACR sampling is a whiz-bang presentation from a bio-engineer at MIT. Oliver Jonas, a postdoctoral fellow, reported on a device that could one day guide treatment selection for cancer patients.

Jonas has been working on an implantable cylinder of less than a millimeter across and 4 millimeters long that possesses multiple reservoirs that can accommodate micro-doses of drugs, or drug combinations. The device is loaded with the chosen therapeutics, and implanted in a tumor via standard biopsy needle.

Once the device is retrieved along with some surrounding tumor tissue, the tissue is then assayed for drug activity. Precise imaging allows for activity in a given region of the sample to be traced back to the drug that was dispersed.

To date, over 100 compounds have been analyzed in mouse models with numerous tumor types. “In this way we can test the phenotypic drug response to a large number of agents in parallel within a single tumor in 1-2 days,” said Jonas.

Were that capability not impressive enough, the next-generation device will be tethered to fiber optics, and use molecular reporters which will enable real time, in vivo assessment of drug activity.

Though still in early development the device has already received a significant stamp of validation, as it is currently being tested in the laboratory of Jose Baselga, cancer researcher, and current president of the Memorial Sloan Kettering Cancer Center.